Arteriosclerosis is a disease frequently found in aorta, coronary arteries, cerebral arteries, and carotid arteries, being a main cause of myocardial infarction and cerebral infarction. At present, the presence of atherosclerosis is said to be crucial for the ground of the onset of ischemic organ diseases such as ischemic heart disease and cerebrovascular disorder, which are top leading causes of death. Arteriosclerotic lesions are pathomorphologically characterized by: fatty streaks which are subendothelial accumulations of cholesterol ester-storing cells (foam cells); and as an advanced stage thereof, invasions of smooth muscle cells, macrophages, T cells, and the like; as well as fibrous plaques showing cellular necrosis and fat accumulation. The site with fat accumulation is structurally fragile, where plaques are ruptured, triggered by a hemodynamic force, and thereby a thrombus is rapidly formed by reactions of tissue factors and blood coagulation factors. It has been elucidated that the occurrence of thrombotic blockage by the rupture of plaques in a coronary artery is closely associated with the onset of so-called acute coronary syndromes such as acute myocardial infarction, unstable angina pectoris, and cardiac sudden death (Non-Patent Document 1)
Arteriosclerosis is gradually developed without subjective symptoms, and all of the sudden, myocardial infarction, cerebral infarction, or angina pectoris occurs. Thus, early stage detection is required. So far, ultrasonography, angiography, imaging tests with MRI (magnetic resonance imaging devices) or such a device, electrocardiography, electroencephalography, and the like have been widely carried out for the diagnosis of arteriosclerotic lesions. However, methods by means of biochemical examination have been demanded so that diagnosis of an arteriosclerotic lesion can achieve an early detection.
In the diagnosis of an arteriosclerotic lesion by means of biochemical examination, there has been known measurements of arteriosclerosis-induced lipoproteins which are associated with lipid accumulation in the vascular wall such as LDL (low density lipoprotein), lipoprotein (Lp-α), remnant lipoprotein, and oxidized LDL in serum or plasma. In particular, measurement of arteriosclerosis-associated substances in blood are attracting attention in recent years. It is reported that measurement of an inflammatory substance: CRP (C-reactive protein), and measurement of the chlamydia antibody titer are useful.
As for the diagnosis method of an arteriosclerotic lesion by means of such measurement of an arteriosclerosis-induced lipoprotein, the following methods are known. For example, regarding the LDL measurement, the followings have been proposed: measurement of neutrophil, monocyte/macrophage or like inflammatory cell-originated components such as lactoferrin, myeloperoxidase, granulocytic elastase in serum or plasma, forming a complex with the oxidized LDL existing in the serum or the plasma, by an immunological means (Patent Document 1); use of an immunoassay method with a fused polypeptide comprising the extracellular region of an oxidized LDL receptor and a part of the heavy chain constant region of an immunoglobulin (Patent Document 2); use of an anti-human aldehyde-modified α1 antitrypsin monoclonal antibody capable of specifically recognizing oxidized LDL-α1 antitrypsin complex (Patent Documents 3 and 4); measurement of the degree of oxidative denaturation of LDL in plasma by an oxidizing agent comprising an azo compound such as V-70 (Patent Document 5); and the like.
Furthermore, regarding the diagnosis of an arteriosclerotic lesion by means of lipoprotein measurement, the followings have been disclosed: measurement of remnant lipoprotein (RLP) in denatured blood (Patent Document 6); diagnosis of rheumatoid or arteriosclerotic lesions through detection of the expression of the human cartilage GP39-L polypeptide gene (Patent Document 7); diagnosis of arteriosclerotic lesions through measurement of apoB100 lipoprotein in blood (Patent Document 8); measurement of human phospholipid transfer protein (PLTP) with use of a monoclonal antibody against PLTP (Patent Document 9); use of an apo lipoprotein A-I antibody as a marker for diagnosing arteriosclerosis (Patent Document 10); and the like.
In addition, regarding other means related to the diagnosis of an arteriosclerotic lesion, the followings have been proposed: diagnosis of hyperlipemia or arteriosclerotic lesions with use of an antibody against a sodium dependent bile acid transporter protein (Patent Document 11); diagnosis through measurement of the coagulation factor VII-activating protease (FSAP) as a risk factor for atherosclerosis (Patent Document 12); examination of arteriosclerosis through detection of an endothelial and smooth muscle cell-derived neuropilin-like molecule (ESDN) or the gene expression thereof (Patent Document 13); use of an anti-human hepatic triglyceride lipase antibody (Patent Document 14); diagnosis of arteriosclerotic lesions by using the serotonin concentration in a plasma sample as a marker (Patent Documents 15 and 16); and the like.
Furthermore, regarding yet other means related to the diagnosis of an arteriosclerotic lesion, the followings have been proposed: diagnosis of chronic renal failure or atherosclerosis by using, as the analyte, an sMAD3 polypeptide which is an iso-form of MAD required for the signal transduction of DPP which is a TGF-family member of cytokine/growth factor (Patent Document 17); measurement of a complex of Lp-α and α2-macroglobulin/interleukin 6 in blood as the analyte by an immunological means using an antibody thereof (Patent Document 18); use of a monoclonal antibody against a paraoxonase (Patent Document 19); detection of arteriosclerosis through measurement of a saturated ultra long-chain fatty acid (Patent Document 20); diagnosis of atherosclerosis by using an RC-9 protein and an antibody thereof (Patent Document 21); and the like.
In this way, many methods have been proposed regarding the biochemical examination related to the diagnosis of an arteriosclerotic lesion. However, most of the detection markers of them are risk markers. For more radical and specific diagnosis of an arteriosclerotic lesion, an advanced development of markers capable of specifically detecting such a lesion has been demanded.
Therefore, Patent Document 22 has proposed, as a marker for specifically detecting an arteriosclerotic lesion, a polypeptide marker for diagnosing arteriosclerosis, a gene marker for diagnosing arteriosclerosis, an antibody specifically bindable to the polypeptide marker for diagnosing arteriosclerosis, a probe for detecting the gene marker for diagnosing arteriosclerosis, and a method for detecting an arteriosclerotic lesion.    Patent Document 1: Japanese Unexamined Patent Application, First Publication No. 2002-48790    Patent Document 2: Japanese Unexamined Patent Application, First Publication No. 2002-17353    Patent Document 3: Japanese Unexamined Patent Application, First Publication No. 2000-184885    Patent Document 4: Japanese Unexamined Patent Application, First Publication No. H10-142226    Patent Document 5: Japanese Unexamined Patent Application, First Publication No. H9-203736    Patent Document 6: Japanese Unexamined Patent Application, First Publication No. 2002-181820    Patent Document 7: Japanese Unexamined Patent Application, First Publication No. 2002-142781    Patent Document 8: Japanese Unexamined Patent Application, First Publication No. 2002-55106    Patent Document 9: Japanese Unexamined Patent Application, First Publication No. H11-346782    Patent Document 10: Japanese Unexamined Patent Application, First Publication No. H8-160042    Patent Document 11: Japanese Unexamined Patent Application, First Publication No. 2003-310281    Patent Document 12: Japanese Unexamined Patent Application, First Publication No. 2003-304873    Patent Document 13: Japanese Unexamined Patent Application, First Publication No. 2003-189872    Patent Document 14: Japanese Unexamined Patent Application, First Publication No. 2002-308900    Patent Document 15: Japanese Unexamined Patent Application, First Publication No. 2002-277461    Patent Document 16: Japanese Unexamined Patent Application, First Publication No. 2002-131313    Patent Document 17: Japanese Unexamined Patent Application, First Publication No. 2002-238589    Patent Document 18: Japanese Unexamined Patent Application, First Publication No. 2001-249128    Patent Document 19: Japanese Unexamined Patent Application, First Publication No. 2000-333674    Patent Document 20: Japanese Unexamined Patent Application, First Publication No. 2000-206113    Patent Document 21: Published Japanese translation No. 2000-503764 of PCT International Publication    Patent Document 22: Japanese Unexamined Patent Application, First Publication No. 2005-168498    Non-Patent Document 1: N. Eng. J. Med., 326, 242-250, 1992,    Non-Patent Document 2: Journal of Biological Chemistry, 272, 556, 1997.
According to the technique of Patent Document 22, an arteriosclerotic lesion can be detected with easy manipulation, and an early detection of arteriosclerosis can be expected. However, it does not satisfy an adequate level. There has been a demand for more accurate detection of an arteriosclerotic lesion with use of a greater number of polypeptide markers for diagnosing arteriosclerosis, gene markers for diagnosing arteriosclerosis, and the like.
Therefore, it is an object of the present invention to provide polypeptide markers for diagnosing arteriosclerosis, gene markers for diagnosing arteriosclerosis, antibodies, probes for detecting an arteriosclerosis marker gene, a DNA microarray or a DNA chip for detecting an arteriosclerosis marker gene, a method for detecting arteriosclerosis, and a kit for diagnosing arteriosclerosis, with which an arteriosclerotic lesion can be detected with much improved accuracy.